Continuing Education Activity

Rufinamide is one of the anti-seizure drugs (ASD) used as an add-on therapy to treat seizures associated with Lennox Gastaut syndrome, and it is structurally unrelated to other traditional ASDs. This CME activity provides a brief and illustrative review of this drug's FDA-approved indications and pharmacodynamic and pharmacokinetic properties. This activity will also highlight the side effects, contraindications, and dosing regimens of this drug and will also discuss the practice parameters of the American Academy of Neurology guidelines regarding the utility of this drug in clinical practice.

Objectives:

• Outline the common drug-drug interactions in a patient with Lennox Gastaut syndrome who starts on rufinamide therapy.

• Summarize the common and serious adverse effects associated with rufinamide.

• Review the pharmacodynamic and pharmacokinetic properties of rufinamide.

• Explain how an interprofessional team approach to rufinamide therapy can improve patient outcomes.

Indications

Rufinamide is a tri-azole derivative drug structurally unrelated to any other anti-seizure drug (ASD).[1] It was developed first in 2004 and later was granted an orphan drug status in October 2004, and was first marketed in Europe in January 2007. It was approved by the US FDA on November 14, 2008, for the adjunctive treatment of seizures associated with Lennox Gastaut syndrome (LGS).[2] Interestingly, it was the first anti-seizure medication to reach the US market with a pediatric indication prior to approval for adults.

FDA Indication: Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in pediatric patients one year of age and older and adults.

Mechanism of Action

Rufinamide (1-[(2,6-difluorophenyl] methyl))-1hydro-1,2,3-triazole-4 carboxamide) has a tri-azole group within its structure, which has a structural resemblance to anti-fungal and fungicidal drugs; however, rufinamide has no structural similarity to any of the anti-seizure medications.

The exact mechanism of action of rufinamide is unknown. In vitro, it stabilizes the inactive state of the sodium channel, limiting the sustained bursts of high-frequency action potentials and preventing sodium channels from returning to an activated state, therefore decreasing the neuronal hyperexcitability and action potential propagation.[3] In this way, it modulates the activity of the sodium channel, prolonging its inactivity. Rufinamide has no effect on benzodiazepine, gamma-aminobutyric acid (GABA) receptors, or adenosine uptake and has no interactions with glutamate, adrenergic, tryptophan, histamine, and muscarinic cholinergic receptors.[2]

Administration

Rufinamide is available as a suspension of 40 mg/mL.

Rufinamide administration iv via twice-daily dosing. In children, it is started at 10 mg/kg/day and is gradually increased by 10 mg/kg every other day to 45 mg/kg/day or 3200 mg/day (whichever is less). In adults, the dosing regimen begins with 400 to 800 mg/day, gradually increasing by 400 to 800 mg every other day, up to a maximum of 3200 mg/day. Rufinamide is administered orally and is available in two formulations: Film-coated tablets (200 mg, 400 mg) and oral suspension (40 mg/ml). If on valproic acid, the US labeling recommends that the initial rufinamide dose be 400 mg daily (<10 mg/kg/day) due to the enzyme inhibition effects of valproic acid.[4]

Rufinamide has a slow absorption (T-max 4 to 6 hours) and exhibits bioavailability of up to 85%.[1] The bioavailability is better when taken with food. The half-life of rufinamide is 6 to 10 hours and has relatively low protein binding, 26 to 34%, and binds primarily to albumin, thus having few displacement drug-drug interactions. It is metabolized via a non-CYP450 pathway by carboxylase-mediated hydrolysis in the liver into its inactive metabolite. It is primarily excreted, up to 85% from kidneys, and 2% is excreted unchanged in the urine. No dose adjustment is necessary for renal impairment.[2]

Patients with renal impairment will require no dosing adjustments. Clinicians can give 30% of the usual dose as a post-dialysis supplement for hemodialysis patients. Peritoneal dialysis dosing is undefined. Caution is advised in patients with mild to moderate hepatic impairment; with severe impairment, the recommendation is to avoid using rufinamide.

Adverse Effects

The common adverse effect of rufinamide includes somnolence, vomiting, headache, fatigue, dizziness, nausea, and rarely, flu-like symptoms, nasopharyngitis, rash, ataxia, and diplopia.

Four less common but potentially significant adverse effects related to rufinamide are shortening QT interval, multi-organ hypersensitivity/drug reaction with eosinophilia and systemic symptoms (DRESS), leukopenia, and Stevens-Johnson syndrome.[5][6] Other potentially serious adverse reactions include seizures with abrupt withdrawal of the drug, suicidality, and status epilepticus.[7]

The QT interval shortening below 300 was not observed in the studies with doses up to 7200 mg per day. There was no sign of drug-induced sudden death or ventricular arrhythmias with rufinamide. However, in patients with a history of familial short QT syndrome, rufinamide was associated with an increased risk of sudden death and ventricular arrhythmia/fibrillation. Such events tend to occur when the QT interval falls below 300 msec. Therefore, caution is also necessary with the concomitant use of rufinamide with other potential drugs that shorten the QT interval.[5]

In the clinical trials, DRESS is most commonly seen in children less than 12 years of age; it occurred within four weeks of rufinamide initiation and resolved or improved with discontinuation of the drug. Therefore, if there is an index of suspicion of DRESS, the patient should undergo evaluation, and rufinamide should be discontinued and alternative treatment initiated.

Contraindications

The major contraindication to the use of rufinamide is familial short QT syndrome. As discussed above, rufinamide was associated with significant ventricular arrhythmia, including cardiac death in patients with a history of short QT syndrome. Other contraindications include hypersensitivity to the drug or any components of the formulation.

Minor contraindications include concomitant use of rufinamide with other potential drugs that shorten QT interval and the presence or history of the short QT interval; therefore, the recommendation is to routinely check the QT interval in these patient populations. Other contraindications include hypersensitivity to rufinamide and/or triazole derivatives.

Warnings /precautions include central nervous system (CNS) effects, including cognitive and coordination dysfunction. Therefore, caution is necessary regarding participating in tasks that require mental alertness. Other warnings/precautions include multi-organ hypersensitivity reactions (like DRESS, as discussed above), dermatological reactions such as Steven Johnson syndrome (SJS), leukopenia, and suicidal ideation.

Hepatic impairment: Rufinamide is not recommended for use in severe hepatic impairment; however, caution is advised in mild to moderate hepatic impairment.

Rufinamide is a Pregnancy Category C drug, so clinicians need to weigh the risks vs. benefits of using rufinamide during pregnancy; it is likely to be excreted in human milk. However, there is no contraindication to breastfeeding with rufinamide use.[8]

Monitoring

In general, Rufinamide does not require routine ancillary monitoring except for the clinical evaluation, such as seizure frequency and duration. As with other AEDs, patients can experience behavioral changes and/or suicidal ideation and dermatological reactions, eg, rash.[9]

There are no well-established therapeutic levels of rufinamide. In one of the clinical trials, the plasma concentration for rufinamide ranged from 4.95 to 48.15 ug/ml during the maintenance period.[10]

In general, the drug-drug interactions with rufinamide are very limited.[1] The primary significant adverse drug-drug interaction of rufinamide, which is clinically significant, is with valproic acid, which is an enzyme inhibitor and can significantly decrease rufinamide clearance by 60-70%, thus increasing rufinamide levels, especially in the pediatric population, thus lowering rufinamide levels, especially in the pediatric population. Other contraindicated agents for concurrent use with rufinamide include amifampridine, bupropion, and metoclopramide.[11]

Rufinamide itself is a weak inducer of CYP3A4 iso-enzyme. Still, it has few drug-drug interactions with other AEDs, which metabolize through the same enzyme system as carbamazepine oxcarbazepine, zonisamide, tiagabine, topiramate, etc. The P450 enzyme inducers (like phenytoin and phenobarbital) can decrease rufinamide levels by 25 to 45%. Rufinamide can render oral contraceptive pills (OCP) less effective by increasing their clearance, especially ethinyl estradiol, norethindrone, and triazolam.[12]

Toxicity

There is no specific antidote for treating rufinamide toxicity. Hemodialysis can cause limited clearance of rufinamide; therefore, no specific evidence is available for a rufinamide toxicity antidote except for general maneuvers for removing unabsorbed medication (emesis, gastric lavage, airway protection, etc.).[13]

Enhancing Healthcare Team Outcomes

Rufinamide is one of the newer generation anti-epileptic medications, which initially was granted an orphan drug status and later got FDA approval for add-on therapy for seizures associated with Lennox Gastaut syndrome in children older than > one year and in adults. American Academy of Neurology (AAN) published updates on practice parameters in treatment-resistant epilepsy in 2018, in which two Class I studies were reviewed.[14] There was a significant reduction in drop attacks, a change in median tonic-atonic seizures, median total seizure frequency, and an increase in responder rates when compared with placebo.

For treatment-resistant adult focal epilepsy (TRAFE), three class I studies were reviewed by AAN, and updates on practice parameters were published in 2018.[14] Rufinamide demonstrated effectiveness with a reduction in median seizure frequency, > 50% responder rate, but benefits were modest.

For the treatment of other childhood epileptic encephalopathies other than LGS, one study found rufinamide may be an effective and better-tolerated add-on therapy for the treatment of refractory childhood-onset epileptic encephalopathies other than LGS and was the most effective in patients with drop-attacks.[15]

To conclude, rufinamide has FDA approval and is effective for add-on therapy for seizures associated with LGS in children older than 1 year and adults. It is also effective in TRAFE and potentially effective in other childhood epileptic encephalopathies other than LGS. It is generally well tolerated with minimal other AED drug-drug interactions. It is contraindicated in familial QT syndrome, and precautionary measures are necessary when using rufinamide with other drugs that prolong QT interval. Since no generic formulation is available to date, the drug is expensive and poses financial issues.

When using rufinamide, employing an interprofessional healthcare team approach to therapy is prudent and beneficial. This team includes clinicians (MDs, DOs, NPs, and PAs), specialists, nursing staff, and pharmacists, all exercising open lines of communication and operating from the same patient data. When the prescribers initiate therapy, they should have a complete patient history to preclude familial short QT syndrome, and it is beneficial to have the nurse review dosing and alert the patient or parents regarding potential adverse events. The pharmacists can reinforce proper dosing and administration schedules when counseling the patient and should be available to address any potential side effects, reporting these to the prescriber or nursing so remedial action can be initiated. This interprofessional team approach to care when using rufinamide (as with any therapeutic intervention) will yield improved patient outcomes and reduce adverse events and therapeutic failure. [Level 5]